Chronic
LeukemiaIntroduction:
There are three major disease entities among chronic leukemias: chronic
lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) and myelodysplastic
syndrome (MDS). Some facts about bone marrow The
soft tissue inside the long bones, the pelvic bones, the vertebral bodies and
the breast bone (sternum) is called bone
marrow (see image).This is the tissue, which regenerates all the
blood cells and there is a finely tuned balance between the circulating blood
cells and the reservoir of the bone marrow. It is important to recognize that
all of the blood cells originate from stem cells, which are immature cells distributed
throughout the bone marrow . All of the other blood cells are derived from these
stem cells. The lymphocytes are the immune cells of the body. They fight infection
in two ways: through the antibody producing B cells and through the T cells. The
B cells are lymphocytes producing antibodies against bacteria and viruses. The
T cells, which are lymphocytes that matured with the help of the thymus gland,
fights cancer cells, parasites and transplants that are mismatched. Both B cells
and the T cells came from the same stem cell. Granulocytes are the major bulk
of the white blood cells and they are the major component of pus cells that will
combat bacteria and are involved in wound healing. They are formed under the influence
of the "colony stimulating factor", a kind of tissue hormone, which
programs the stem cells to differentiate into granulocytes. The hormone erythropoietin
from the kidney will stimulate stem cells to develop into a red blood cell. And
finally, the platelets are derived from the stem cell via a precursor cell called
megakaryocyte. In the following outline we are dealing with cancers of the lymphocyte
origin ( CLL) and the granulocyte origin( CML). The MDS involves various precursor
cells of the bone marrow (Ref. 1 and 2).
General remarks regarding chronic leukemia
CLL occurs mostly in older people (aged more than 60 years)
and is twice as frequent in men than in women. CLL is rare in Japan and China.
It can be found more frequently in some families and when one family member is
diagnosed with it, other first-degree family members have a threefold risk for
CLL or another blood disorder. CLL has an age related risk of occurrence: between
the age of 35 and 59 there is an incidence of 5 per 100, 000 persons in the US,
but at age 80 to 84 this increases to 30 per 100,000 persons, a 6-fold increase.
No link of radiation has been established with CLL, nor is there any known leukemia
virus that would cause it. CML occurs in either sex and
is a leukemia of middle age (most common around age 45 years). It is uncommon
before 10 years of age. In this leukemia 95% of patients have a chromosome marker
at the chromosome 22 (called "Philadelphia chromosome"), which is characteristic
for this type of leukemia. A chromosomal translocation at this chromosome is believed
to be the cause of CML. From this point on it takes an average of 4 years before
a blast crisis occurs. At that point more than 30% of the normal bone marrow cells
have been replaced by blast cells and severe anemia and low platelet counts occur
at the same time. This is so, because the leukemia cancer cells destroy the
red blood cell and platelet precursors in the bone marrow. This can result in
severe bleeding (due to low platelet counts), weakness as well as proneness to
infections (low red blood and immune cell counts). At that critical blast crisis
hundreds of thousand of blast cells per cubic millimeters will travel in the blood
stream and invade vital organs such as the brain, kidneys, lungs and liver. The
mean median survival time after blast crisis is only about 2 months. It can
be extended to about 10 months, if remission can be achieved. With the introduction
of interferon therapy we have a mechanism to delay or prevent the development
of the blast crisis. Survival rates have increased from about 3.5 years before
interferon therapy to about 7 years. However, early diagnosis is necessary. Despite
best efforts this was the best until spring of 2001 that medicine could offer.
But as pointed out below, with the new tyrosine
kinase inhibitors, such as Gleevec, an exciting possibility has opened
up to cure this terrible disease.
Gleevec
- The "New Kid On The Block" To Treat CML: |
| Genetically based therapies are the only hope for a
longterm solution. New research is starting to come out regarding this. A case
in point is the new medicine, which was called STI 571 and has been released in
May 2001 by the FDA under the trade name of "Gleevec". It is a tyrosine
kinase inhibitor. Molecular biological research has shown in the past that CML
cells have a modified gene, which activates the production of tyrosine kinase
that in turn is responsible for the rapid cell division. It follows from this
that a medication that would inhibit this enzyme should stop CLL cells from growing.
The beauty of this line of research is that everything worked as planned and the
human studies to show its safety and effectiveness have been done (Ref.3 and 4).
The data show that this new medication is safe, has few side-effects and that
it also is effective against CML with 53 out of 54 patients having shown a complete
remission (Ref. 3). | MDS is a group
of syndromes often seen in patients older than 50 years. There may be in some
patients a history of benzene exposure
or radiation exposure. The
hall mark of this syndrome is that immature bone marrow stem cells
(hematopoietic
stem cells) of a certain lineage (red blood cells, white blood cells or platelet
precursor cells) suddenly decide to multiply in the sense of cell clones. This
means that one type of cell suddenly takes off by producing millions of "look-alikes".
A high percentage of the MDS patients convert into AML. The response of MDS and
AML to chemotherapy shows a survival, which is very similar, supporting the belief
that MDS may largely be a precursor of AML, although there are other leukemias
lumped in such as Philadelphia negative CML, refractory anemias and some other
more rare hematological disorders. A hematologist needs to be involved in all
of these diseases.
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